■Neddylation(NAE)抑制,影响翻译后蛋白质的功能和周转,是一种很有前途的癌症治疗方法。我们报告了胶质母细胞瘤(GBM)临床前模型的一部分对NAE抑制剂的细胞毒性脆弱性,并确定了差异反应的遗传改变和生物学过程。
■GBMDNA测序和转录组数据查询与NAE抑制反应相关的基因;候选物通过分子技术验证。多组学和功能测定揭示了与NAE抑制反应有关的过程。
■转录组学和shot弹枪蛋白质组学描绘了PTEN信号传导,DNA复制,和DNA修复途径作为敏感和抗性模型之间的显著差异。MLN4924,NAE抑制剂的脆弱性,与S期种群升高有关,DNA再复制,和DNA损伤。在一组GBM模型中,WTPTEN的缺失与对不同NAE抑制剂的抗性相关。NAE抑制应答基因集合可以分离对MLN4924最具抗性的GBM细胞系。
■WTPTEN的丧失与对GBM中抑制NAE的3种不同化合物的不敏感性有关。主要由DNA复制基因组成的NAE抑制反应基因集可以分离对NAEi最具抗性的GBM细胞系,并且可能是未来在精确医学范式中开发脆弱性和临床试验招募的NAE抑制特征的基础。
UNASSIGNED: Neddylation (NAE) inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report the cytotoxic vulnerability to NAE inhibitors in a subset of glioblastoma (GBM) preclinical models and identify genetic alterations and biological processes underlying differential response.
UNASSIGNED: GBM DNA sequencing and transcriptomic data were queried for genes associated with response to NAE inhibition; candidates were validated by molecular techniques. Multi-omics and functional assays revealed processes implicated in NAE inhibition response.
UNASSIGNED: Transcriptomics and shotgun proteomics depict PTEN signaling, DNA replication, and DNA repair pathways as significant differentiators between sensitive and resistant models. Vulnerability to MLN4924, a NAE inhibitor, is associated with elevated S-phase populations, DNA re-replication, and DNA damage. In a panel of GBM models, loss of WT PTEN is associated with resistance to different NAE inhibitors. A NAE inhibition response gene set could segregate the GBM cell lines that are most resistant to MLN4924.
UNASSIGNED: Loss of WT PTEN is associated with non-sensitivity to 3 different compounds that inhibit NAE in GBM. A NAE inhibition response gene set largely consisting of DNA replication genes could segregate GBM cell lines most resistant to NAEi and may be the basis for future development of NAE inhibition signatures of vulnerability and clinical trial enrollment within a precision medicine paradigm.